Preparation of ambrettolide

ABSTRACT

A process for the preparation of ambrettolide and isomers thereof from 1,9-cyclohexadecadiene. Diepoxidized 1,9cyclohexadecadiene is reduced to a mixture of cyclohexadecadiols and oxidized to the corresponding hydroxy ketones. These, upon oxidation in the presence of a boron trifluoride etherate catalyst, are converted into hydroxy cyclohexadecanolides which are dehydrated to form a mixture of isomers of ambrettolide which can be separated by conventional means, if desired.

United States Patent Mookherjee et al.

PREPARATION OF AMBRETTOLIDE Inventors: Braja D. Mookherjee, Matawan;William 1. Taylor, Summit, both of Appl. No.: 18,684

US. Cl ..260/343, 252/522, 260/348 C,

260/348.5 L, 260/617 M, 260/586 A Int. Cl. ..C07d 9/00 Field of Search..260/343 References Cited UNITED STATES PATENTS 3/1947 Collaud..260/343 [451 Aug. 1, 1972 Primary Examiner-John M. Ford Att0meyBrooks,Haidt & Haffner 5 7] ABSTRACT A process for the preparation ofambrettolide and isomers thereof from 1,9-cyclohexadecadiene.Diepoxidized 1,9-cyc1ohexadecadiene is reduced to a mixture ofcyclohexadecadiols and oxidized to the corresponding hydroxy ketones.These, upon oxidation in the presence of a boron trifluoride etheratecatalyst, are converted into hydroxy cyclohexadecanolides which aredehydrated to form a mixture of isomers of ambrettolide which can beseparated by conventional means, if desired.

1 Claim, N0 Drawings This invention relates to a process for thepreparation of macrocyclic compounds for use in the perfume industry.More specifically, the present invention relates to a process for thepreparation of ambrettolide (cyclohexadecen-7-olide) and isomers thereoffrom 1,9-cyclohexadecadiene. Additionally, this invention relates tonovel macrocyclic compounds, i.e., l,2,9,ldiepoxycyclohexadecane,l,9-cyclohexadecadiol, 1,8- cyclohexadecadiol, 9-hydroxyl-cyclohexadecanone, 8-hydroxy-l-cyclohexadecanone,9-hydroxy-lcyclohexadecanolide. These compounds are useful intermediatesin the synthesis of ambrettolide and isomers thereof.

The macrocyclic compounds, i.e., ambrettolide and isomers thereof,prepared by the process of the present invention are musk odorants andas such are highly desirable. The odor of musk is perhaps the mostuniversally appreciated fragrance and is usually thought of as theanimal note in perfumes. A number of naturally occurring species, bothof animal and vegetable origin, possess musk odors; however, only threeanimal sources have achieved any commercial importance. It is because ofthe high demand and short supply of these naturally occurring muskodorants that numerous attempts have been made since the 1920s tosynthesize compounds which would duplicate these desirable odors.

Ambrettolide naturally occurs in musk ambrette seed oil and is avaluable perfurrie base because of its desirable odor. Ruzicka and Stoll[Helv. Chem. Acta, 17, I609 1928)] show a method for preparingmacrocyclic lactones involving the oxidation of macrocyclic ketones withCaro'sacid (persulfuric acid) to the corresponding lactones.Ambrettolide is said to be prepared by this method. US. Pat. No.2,417,151 discloses a process for the preparation of ambrettolideinvolving intramolecular esterification. In this process sodium6,16-dihydroxypalmitate is condensed with lchloropropanediol-2,3 to formthe glycerol monoester which is treated with sodium acid sulfate toproduce a mixture of unsaturated isomeric glycerol mono-esters. Thismixture is then distilled and worked up to yield a mixture ofunsaturated isomeric large-ringed cyclic lactones including ambrettolidewhich can be separated out, if desired. Other methods for thepreparation of macrocyclic lactones are also known but applicants areunaware of any prior art process in which 1,9-cyclohexadecadiene isutilized as the starting material .for the preparation of ambrettolideand isomers thereof.

It is, therefore, an object of the. present invention to provide a novelprocess fore the preparation of ambrettolide and isomers thereof.

It is a further object of the present invention to pro- THE INVENTIONThese objects are achieved by the process of the present invention whichcomprises the steps of:

l. epoxidizing 1,9-cyclohexadecadiene of the structure and 2. reducingsaid diepoxidized cyclohexadecane to form a mixture ofcyclohexadecadiols of the structures 3. oxidizing saidcyclohexadecadiols to form the corresponding hydroxy ketones of thestructures 4. treating said hydroxy ketones with a peracid in thepresence of a boron trifluoride etherate catalyst to form a mixture ofhydroxy cyclohexadecanolides of the structures and 5. dehydrating saidhydroxy cyclohexadecanolides to obtain the desired mixture ofambrettolide and isomers thereof of the general structure whereinx is 5,6, 7 and 8 and y is 8, 7, 6 and 5, respectively and x plus y equals 13;said mixture can be separated by conventional means, if desired, intothe various isomers, e.g., when x is 5 and y is 8 the lacetone isambrettolide and when x is 7 and y is 6 the lactone is iso-ambrettolide.

The l,9-cyclohexadecadiene utilized as the starting material in theprocess of the present invention may be prepared by dimerizingcyclooctene as more fully disclosed in US. Pat. No. 3,439,056, grantedon Apr. 15, 1969.

The first step of the process of the present invention comprisestreating 1,9-cyclohexadecadiene with an excess of an oxidizing agentsuch as a peracid, for example, peracetic acid, perpropionic acid,perbenzoic acid, perphthalic acid or other suitable peracid, in thepresence of an alkali metal carboxylate such as sodium acetate and in asuitable reaction medium at a reduced temperature. Suitable reactionmedia include methylene chloride, chloroform, carbon-tetrachloride, andthe like. Usually, a reduced temperature of from about C to about C isused although a temperature of from 0C to about 5C is preferred. Theperacid oxidizing agent is utilized in excess and preferably in a molarratio of peracid oxidizing agent to l,9-cyclohexadecadiene of at least4:1 to insure completion of the reaction. Thel,2,9,lO-diepoxycyclohexadecane may be separated and recovered byconventional techniques including evaporation, distillation, solventextraction and the like.

The second step of the process comprises treating1,2,9,IO-diepoxycyclohexadecane with an excess of a reducing agent suchas lithium aluminum hydride or hydrogen (in the presence of platinum orpalladium) in a solvent such as ether, methanol, or the like. Thereducing agent is utilized in a molar ratio of reducing agent to1,2,9,lO-diepoxycyelohexadecane of at least about 4:1 to insure acomplete reduction of the diepoxide. The temperature of the reaction ispreferably room temperature and the reaction is usually completed withinfour hours and the reaction mixture is then treated with cold water todecompose the complex formed. The mixture of 1,9- andl,8-cyclohexadecadiols may be recovered by conventional means.

The third step of the process involves oxidizing the 1,9- andl,8-cyclohexadecadiols to the corresponding hydroxy ketones with asuitable oxidizing agent such as chromic acid. This is generallyaccomplished in the presence of a strong mineral acid such as sulfuricacid in a liquid medium such as acetone. The oxidizing agent is utilizedin a molar ratio of oxidizing agent to cyclohexadecadiol of 1:1 toinsure formation of the desired hydroxy ketone. The reaction temperatureis maintained at 5C or less and preferably is at 0C. The mixture of9-hydroxy-lcyclohexadecanone and 8- hydroxy-l-cyclohexadecanone obtainedis recovered by conventional techniques including aqueous extraction,evaporation and distillation.

The fourth step of the process comprises treating the mixture of9-hydroxy-l-cyclohexadecanone and 8- hydroxyl cyclohexadecanone with aperacid oxidizing agent such as peracetic acid, perpropionic acid,perbenzoic acid, perphthalic acid or other suitable peracid in thepresence of a boron trifluoride etherate catalyst and in a suitablereaction medium such as chloroform. The peracid oxidizing agent isutilized in excess and preferably in a molar ratio of peracid to hydroxycyclohexadecanone of at least 3:], preferably about 4:1, to insurecompletion of the reaction. The reaction temperature may vary from about40C to about 70C although preferably it is within the range of about 45Cto about 55C. The mixture of hydroxy cyclohexadecanolides may berecovered in any conventional manner. This step is more fully disclosedin the copending application, Mookherjee and Taylor, Process for thePreparation of Macrocyclic Lactones, Ser. No. l8,70l filed Mar. ll,1970, now abandoned and continued as application Ser. No. 156,955 filedJune 25, 1971 which is incorporated by reference herein.

The fifth step of the process comprises dehydrating the hydroxycyclohexadecanolides to form ambrettolide and isomers thereof. This isconveniently performed with a strong acid catalyst such asp-toluenesulfonic acid, sulfuric acid and the like and is accomplishedin the liquid phase using an anhydrous solvent such as anhydrousbenzene. Temperatures of from about 100C to about 350C, preferably about310C, are necessary to effect the reaction. A mixture of ambrettolideand isomers thereof, is recovered by conventional means and can beseparated, if desired. Separation of the mixture yields a variety ofisomers including ambrettolide and iso-ambrettolide.

The mixture of isomers, as well as ambrettolide (cyclohexadecen-7-olide)and the other isomers individually, prepared by the process of thepresent invention, have a highly desirable and useful odor characterizedas a musk odor and usually thought of as the animal note in perfumes.They can be utilized as a component of perfume compositions to promotemusk fragrances. Perfume compositions containing from about 1.0 percentto about 50.0 percent of these musk odorants by weight based on theactive fragrance ingredients before dilution are desirable and useful.

The following examples will illustrate in detail the manner in which theinvention may be practiced. It will be understood, however, that theinvention is not confined to the specific limitations-set forth in theindividual examples but rather to the scope of the appended claims.

EXAMPLE 1 Preparation of Ambrettolide and isomers Thereof A. Preparationof l,2,9,l0-diepoxycyclohexadecane from l,9-cyclohexadecadiene Anapparatus consisting of a 100 ml reaction flask fitted with athermometer, mechanical stirrer, addition funnel and ice bath is chargedwith 5.0 g (0.023 mole) of l,9-cyclohexadecadiene, 7.0 g of sodiumacetate and 30 ml of methylene chloride and cooled to 0C. A solutioncontaining 9.4 g (0.046 mole) 40 percent peracetic acid and 20 ml ofmethylene chloride is prepared and is then added slowly to the flaskduring a one-half hour period while the temperature is maintained at 0C.The mixture is then stirred for three hours at 0-5C and then ispermitted to return to room temperature. The mixture is then poured intoa separatory funnel containing 40 ml of water. The aqueous layer isextracted three times with 30 ml portions of methylene chloride. Thecombined organic layer is then washed with a saturated sodium chloridesolution until it tests neutral and then is dried over anhydrous sodiumsulfate. The solvent is removed by means of a rotary evaporator yielding6.16 g of crude material which is then chromatographed to obtain 5.15 gpercent yield) of 1,2,9, 1 O-diepoxycyclohexadecane.

B. Preparation of a mixture of l,9-and l,8-cyclohexadecadiols from 1,2,9, l O-diepoxycyclohexadecane An apparatus consisting of a l 1.reaction flask fitted with an addition funnel, thermometer, mechanicalstirrer, condenser, heating mantle and nitrogen purge is charged with12.14 g (0.32 mole) of lithium aluminum hydride and 300 ml of anhydrousether. A solution containing 20.0 g (0.079 mole) ofl,2,9,l0-diepoxycyclohexadecane and 200 ml of anhydrous ether is thenadded slowly over a one hour period. After the addition is completed themixture is refluxed for four hours and then cooled down to 4C. Thereaction mixture is then decomposed with 40 ml of cold water and thelithium hydroxide salt is extracted and washed with carbon tetrachlorideuntil neutral and the ether extract is washed three times with 50 mlportions of a 50 percent sodium chloride solution until neutral. Thesolvent is then removed yielding 15.6 g of a crude cyclohexadecadiolmixture. C. Preparation of a mixture of 9-hydroxy-l-cyclohexadecanoneand 8'hydroxy-l-cyclohexadecanone from 1,9- and 1,8-cyclohexadecadiolsAn apparatus consisting of a l 1. reaction flask fitted with an additionfunnel, reflux condenser, thermometer, mechanical stirrer and dry icebath is charged with 14.0 g (0.956 mole) of a mixture of 1,9- and 1,8-cyclohexadecadiol and 550 ml of acetone and cooled to 0C. A solutioncontaining 5.6 g (0.056 mole) of chromic oxide, 4.2 g of concentratedsulfuric acid and 28 ml of water is prepared and added dropwise over a 2hour period. After the addition is completed the reaction mixture isstirred for 1 hour at 0C and then the acetone is removed by vacuum andreplaced with 400 ml of water. The aqueous solution is then transferredto a separatory funnel and saturated with sodium chloride and thenextracted five times with 100 ml portions of carbon tetrachloride. It isthen washed three times with a 50% sodium chloride solution untilneutral and then dried over sodium sulfate yielding 12.6 g of crudematerial. This crude material is then chromatographed to obtain 5.2 g(41 percent yield) of hydroxy cyclohexadecanones. D. Preparation of amixture of 9-hydroxy-l-cyclohexadecanolide,8-hydroxy-l-cyclohexadecanolide and l O-hydroxyll -cyclohexadecanolidefrom 9-hydroxyl cyclohexadecanone and S-hydroxyl-cyclohexadecanone Anapparatus consisting of a 100 ml reaction flask fitted with an additionfunnel, mechanical stirrer, thermometer, reflux condenser, heatingmantle and thermo watch is charged with 2.0 g (0.0078 mole) of a mixtureof hydroxy cyclohexadecanones, 40 ml of chloroform and 0.6 g of borontrifluoride etherate and the mixture is stirred. Over a minute period, 5g (0.028 mole) of 40 percent peracetic acid is added and the resultingreaction mixture is then stirred for 12 hours at C i 5C and then for 24hours at room temperature. The chloroform layer is then washed threetimes with 20 ml portions of a 50 percent sodium chloride solution andtwice with cold water until neutral and then dried over sodium sulfateyielding 2.0 g of crude material. This crude material is thenchromatographed to obtain 0.35 g (30 percent yield) of hydroxycyclohexadecanolides. E. Preparation of ambrettolide from hydroxycyclohexadecanolides An apparatus consisting of a 15 ml receiver fittedwith an addition funnel, glass stopper and magnetic stirrer is chargedwith I00 mg of a mixture of hydroxy cyclohexadecanolides, 1 ml ofanhydrous benzene and 30 mg of p-toluene sulfonic acid and the mixtureis stirred for one hour at room temperature. The reaction mixture isthen injected into a pyrolytic glass column packed with 5 g of Anakromcoated with 10 percent silicone rubber (SE 30 Gum Rubber) and l gstainless steel turnings at a temperature of 310C and the distillate iscollected in a cooled vial, and purged of the solvent leaving 50 mg of amixture of ambrettolide and isomers thereof. This mixture is separatedby gas-liquid chromatography using helium as the gas and a 25 foot,one-quarter inch inside diameter stainless steel column at l00C and witha flow rate of ml per minute and packed with 5 percent polyethyleneglycol (carbowax 20M) supported on Anakrom ABS (a trademark of theAnalab Corporation, North Haven, Connecticut covering a treateddiatomaceous earth composition). The analysis shows the presence ofambrettolide as well as the other isomers.

EXAMPLE ll A perfume composition is prepared by admixing the followingingredients in the indicated proportions:

This perfume composition is found to have a desirable musk fragrancequality.

EXAMPLE [I] A total of g of soap chips is mixed with l g of the perfumecomposition prepared in Example ll until a substantially homogeneouscomposition is obtained. This homogeneous mixture is pressed into a barhaving a desirable musk scent.

What we claim is:

l. The process for the preparation of ambrettolide and isomers thereofcomprising the steps of:

a. epoxidizing 1,9-cyclohexadecadiene with an ex- 1 cess of a peracid toobtain 1,2,9,l0-diepoxycyclohexadecane;

b. reducing the l,2,9,lO-diepoxycyclohexadecane with a reducing agent toobtain a mixture of 1,9- cyclohexadecadiol and l,8-cyclohexadecadiol;

c. oxidizing the mixture of l,9-cyclohexadecadiol andl,8-cyclohexadecadiol with an oxidizing agent to obtain a mixture of9-hydroxy-1-cyclohexadecanone and 8-hydroxyl -cyclohexadecanone;

d. oxidizing the mixture of 9-hydroxy-l-cyclohexadecanone and8-hydroxyl-cyclohexadecanone with a peracid in the presence of a borontrifluoride etherate catalyst to obtain a mixture of 7 3 ,68 1 ,3 95 e 89-hydroxy-l-cyclohexadecanolide, 8-hydroxy-le. dehydrating the mixtureof hydroxy cyclohexcyclohexadecanolide andIO-hydroxy-l-cyclohexadecanolides in the presence of a strong acid toadecanolide; obtain ambrettolide and isomers thereof.

